Aripiprazole complex forumlation and method

ABSTRACT

An aripiprazole formulation is provided which includes the antipsychotic agent aripiprazole in the form of an inclusion complex in a β-cyclodextrin, preferably, sulfobutyl ether β-cyclodextrin (SBECD), which in the form of an injectable produces reversible generally minimal to mild irritation at the intramuscular injection site. A method for minimizing or reducing irritation caused by aripiprazole at an intramuscular injection site and a method for treating schizophrenia employing the above formulation are also provided.

CROSS REFERENCE TO RELATED APPLICATION

This Continuation application claims the benefit of U.S. Ser. No.13/656,785 filed Oct. 22, 2012, now pending, which is a Continuationapplication which claims the benefit of U.S. Ser. No. 13/288,077 filedNov. 3, 2011, now abandoned, which is a Continuation application whichclaims the benefit of U.S. Ser. No. 13/046,124 filed Mar. 11, 2011, nowabandoned, which is a Continuation application which claims the benefitof U.S. Ser. No. 12/417,067 filed Apr. 2, 2009, now abandoned, which isa Continuation application which claims the benefit of U.S. Ser. No.11/452,782 filed Jun. 14, 2006, now U.S. Pat. No. 7,550,445, which is aContinuation application which claims the benefit of U.S. Ser. No.10/642,366 filed Aug. 14, 2003, now U.S. Pat. No. 7,115,587, whichclaims the benefit of U.S. Provisional Application Ser. No. 60/404,713filed Aug. 20, 2002, now expired.

FIELD OF THE INVENTION

The present invention relates to an aripiprazole inclusion complex witha substituted-β-cyclodextrin, an aripiprazole formulation which includesaripiprazole in the form of the above inclusion complex, an injectableformulation which contains the above complex of aripiprazole, a methodfor reducing irritation normally caused by aripiprazole at anintramuscular injection site employing the above injectable formulationand a method for treating schizophrenia employing the above formulation.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,006,528 to Oshiro et al. discloses7-[(4-phenylpiperazino)butoxy]carbostyrils, which include aripiprazole,as dopaminergic neurotransmitter antagonists.

Aripiprazole which has the structure

is an atypical antipsychotic agent useful in treating schizophrenia. ithas poor aqueous solubility (<1 μg/mL at room temperature). Whenformulated as an intramuscular (IM) injectable solution, aripiprazolehas been found to cause unacceptable (moderate to severe) tissueirritation at the muscular site with many water-miscible co-solventsystems, and water-immiscible solvent and co-solvent systems such ashexonoic acid: medium chain triglyceride (10:90), polyethylene glycol400:ethanol:lactic acid (35:15:50), benzyl alcohol:sesame oil (10:90),benzyl alcohol:medium chain triglyceride (10:90), benzylalcohol:tributyrin (5:95), and polysorbate 80 in 2.5 mM tartaric acid.

Cyclodextrins are known for their use in increasing solubility of drugs.They function by forming inclusion complexes with hydrophobic molecules.Unfortunately, there are many drugs for which cyclodextrin complexationeither is not possible or produces no apparent advantages as disclosedby J. Szejtli, Cyclodexirins in Drug Formulations:Part II,Pharmaceutical Technology, 24-38, August, 1991.

U.S. Pat. Nos. 5,134,127 and 5,376,645 each to Stella et al, disclosesulfoalkyl ether cyclodextrin derivatives and their use as solubilizingagents for water-insoluble drugs for oral, intranasal or parenteraladministration including intravenous and intramuscular. Stella et al,disclose an inclusion complex of the water-insoluble drug and thesulfoalkyl ether cyclodextrin derivative and pharmaceutical compositionscontaining same. Examples of sulfoalkyl ether cyclodextrin derivativesdisclosed include mono-sulfobutyl ether of β-cyclodextrin andmonosulfopropyl ether of β-cyclodextrin. Examples of water-insolubledrugs are set out in column 7 starting at line 25 and include, amongothers, benzodiazepines, chlorpromazine, diazepam, mephorbarbital,methbarbital, nitrazepam, and phenobarbital.

U.S. Pat. No. 6,232,304 to Kim et al. discloses inclusion complexes ofaryl-heterocyclic salts such as the tartrate salt of ziprasidone in acyclodextrin such as β-cyclodextrin sulfobutyl ether (SBECD), andhydroxpropyl-β-cyclodextrin (HPBCD), and use of such inclusion complexesin oral and parenteral formulations.

Japanese Patent Application No. 09301867A2 dated Nov. 25, 1997 disclosesantidepressant compositions in the form of tablets containingaripiprazole.

EP1145711A1 dated Oct. 17, 2001 (based on U.S. Application Ser. No.2000-547948 filed Apr. 12, 2000) discloses flash-melt oral dosageformulations containing aripiprazole.

U.S. Pat. No. 5,904,929 to Uckama et al. discloses trans-mucosal andtransdermal pharmaceutical compositions containing a drug and aperacylated cyclodextrin as a solubilizing agent. Examples of drugsinclude antidepressants such as amitriptyline HCl, amoxapine,butriptyline HCl, clomipramine HCl, desipramine HCl, dothiepin HCl,doxepin HCl, fluoxetine, gepirone, imipramine, lithium carbonate,mianserin HCl, milnacipran, nortriptyline HCl and paroxetine HCl;anti-muscarinic agents such as atropine sulphate and hyoscine; sedatingagents such as alprazolam, buspirone HCl, chlordiazepoxide HCl,chlorpromazine, clozapine, diazepam, flupenthixol HCl, fluphenazine,flurazepam, lorazepam, mazapertine, olanzapine, oxazepam, pimozide,pipamperone, piracetam, promazine, risperidone, selfotel, seroquel,sulpiride, temazepam, thiothixene, triazolam, trifluperidol andziprasidone; anti-migraine drugs such as alniditan and sumatriptan;beta-adrenoreptor blocking agents such as atenolol, carvedilol,metoprolol, nebivolol and propranolol; anti-Parkinsonian drugs such asbromocryptine mesylate, levodopa and selegiline HCl; opioid analgesicssuch as buprenorphine HCl, codeine, dextromoramide and dihydrocodeine;parasympathomimetics such as galanthamine, neostigmine, physostymine,tacrine, donepezil, ENA 713 (exelon) and xanomeline; and vasodilatorssuch as amlodipine, buflomedil, amyl nitrite, diltiazem, dipyridamole,glyceryl trinitrate, isosorbide dinitrate, lidoflazine, molsidomine,nicardipine, nifedipine, oxpentifylline and pentaerythritoltetranitrate.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided an inclusioncomplex of aripiprazole in a substituted-beta-cyclodextrin. It has beenfound that the inclusion complex of aripiprazole is substantially morewater-soluble relative to the non-complexed aripiprazole.

Surprisingly and unexpectedly, it has been found that when aripiprazoleis complexed with a substituted β-cyclodextrin such as sulfobutylether-β-cyclodextrin, it may be formulated as an injectable whichdelivers aripiprazole to the muscular site with unexpectedly diminishedirritation as compared to injectables containing uncomplexedaripiprazole.

In addition, in accordance with the present invention, a pharmaceuticalformulation is provided which is formed of an inclusion complex ofaripiprazole and a substituted-β-cyclodextrin, and a pharmaceuticallyacceptable carrier therefor.

In a preferred embodiment, the pharmaceutical formulation of theinvention will be in the form of an aqueous parenteral or injectableformulation. However, the pharmaceutical formulation of the inventionmay be in other dosage forms such as lyophilized injectable, oral (forexample tablets, capsules, elixirs and the like), transdermal ortransnaucosal forms or inhalation forms.

Further, in accordance with the present invention, a method is providedfor administering injectable aripiprazole without causing unacceptableirritation at the site of injection wherein the above describedinjectable formulation is administered, preferably intramuscularly, to apatient in need of treatment.

Still further in accordance with the present invention, a method isprovided for treating schizophrenia which includes the step ofadministering to a patient in need of treatment the above describedformulation, preferably in injectable form, without causing undueirritation at the site of injection, whether it be at a muscular site orother site.

DETAILED DESCRIPTION OF THE INVENTION

Aripiprazole has poor water solubility and thus is difficult toformulate as an aqueous injectable. In accordance with the presentinvention, it as been found that the water-solubility of aripiprazolemay be sufficiently increased to allow it to be formulated as an aqueousinjectable by complexing aripiprazole with a substituted-β-cyclodextrin.In effect, the cyclodextrin inhibits precipitation of the aripiprazoleat the site of injection. The aqueous injectable formulation containingthe complex of aripiprazole and the substituted-β-cyclodextrin may beadministered preferably intramuscularly without causing unacceptableirritation at the muscular site. This is indeed surprising andunexpected since, as indicated above, a host of water-miscibleco-solvent systems and water-immiscible co-solvent systems have beenfound to be unacceptable as carriers for injectable aripiprazoleformulations because of the unacceptable irritation profile of suchformulations. On the other hand, the aqueous injectable formulation ofthe invention delivers aripiprazole without causing unacceptableirritation at the site of injection.

As will be seen hereinafter, the aripiprazole formulation in the form ofan aqueous injectable will include an acid buffer and a base to adjustpH to desired levels.

The substituted-β-cyclodextrin suitable for use herein refers tosulfobutyl ether β-cyclodextrin (SBECD) and hydroxypropyl-β-cyclodextrin(HPBCD), with SBECD being preferred.

The term “undue irritation” or “unacceptable irritation” at the site ofinjection or at the muscular site refers to moderate to severeirritation which is unacceptable to the patient and thereby impactsunfavorably on patient compliance.

The term “reduced irritation” at the site of injection or at themuscular site refers to generally minimal to mild irritation which isacceptable to the patient and does not impact unfavorably on patientcompliance.

The aripiprazole will form a complex with the substituted-β-cyclodextrinwhich complex may he dissolved in water to form an injectableformulation. However, physical mixtures of aripiprazole and thesubstituted-β-cyclodextrin are within the scope of the present inventionas well.

The complex or the physical mixture may also be compressed into a tabletor may be filled into capsules.

The aripiprazole formulations of the invention may be formed of dryphysical mixtures of aripiprazole and the substituted-β-cyclodextrin ordry inclusion complexes thereof which upon addition of water arereconstituted to form an aqueous injectable formulation. Alternatively,the aqueous injectable formulation may be freeze dried and laterreconstituted with water. Thus, the inclusion complex in accordance withthe invention, may be pre-formed, formed in situ or formed in vivo (inthe gastrointestional tract or the buccal cavity). All of the above arecontemplated by the present invention.

The aripiprazole formulation of the invention in the form of an aqueousinjectable will include an acid buffer to adjust pH of the aqueousinjection within the range from about 3.5 to about 5. Examples of acidbuffers suitable for use herein include acids such as hydrochloric acid,sulfuric acid, phosphoric acid, hydrobromic acid and the like, andorganic acids such as oxalic acid, maleic acid, fumaric acid, lacticacid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid,methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid,ethanesulfonic acid and the like. Acid salts of the above acids may beemployed as well. Preferred acids are tartaric acid, citric acid, andhydrochloric acid. Most preferred is tartaric acid,

The injectable formulation of the invention will have a pH within therange from about 3.5 to about 5, preferably from about 4 to about 4.6,and most preferably about 4.3. In formulating the injectable, ifnecessary, the pH may be adjusted with a base such as an alkali metalhydroxide such as NaOH, KOH, or LiOH, preferably NaOH, or an alkalineearth metal hydroxide, such as Mg(OH)₂ or Ca(OH)₂.

In preparing the aqueous injectable formulation of the invention, thesubstituted-β-cyclodextrin will be employed in a weight ratio to thearipiprazole within the range from about 5:1 to 400:1, preferably fromabout 10:1 to about 100:1. Each type of cyclodextrin employed requires adifferent ratio to inhibit or prevent precipitation of aripiprazole atthe injection site. In preferred embodiments of the aqueous injectableof the invention, the substituted-β-cyclodextrin will be SBECD whichwill be employed in a weight ratio to aripiprazole within the range fromabout 5:1 to about 400:1, preferably from about 20:1 to about 40:1. Thecyclodextrin may be present in an amount greater than that needed tocomplex the aripiprazole since the additional cyclodextrin could aid indissolution of the aripiprazole.

The aripiprazole will be present in the aqueous injectable formulationin an amount within the range from about 0.1 to about 2.5% by weight,preferably from about 0.2 to about 1.5% by weight based on the totalinjectable formulation.

In preferred embodiments, the aripiprazole will be present in theaqueous injectable formulation to provide from about. 1 to about 20mg/mL of formulation, preferably from about 1.5 to about 8 mg/mL offormulation.

In more preferred embodiments, the formulations of the invention willprovide 2 mg aripiprazole/mL, 5 mg/mL and 7.5 mg/mL. Fill volumes willpreferably be 0.5 mL and 2 mL.

A preferred injectable formulation is as follows:

-   -   (1) aripiprazole in an amount to provide from about 1.5 to about        8 mg/mL of solution.    -   (2) SBECD in an amount from about 100 to about 200 mg/mL of        solution.    -   (3) acid buffer (preferably tartaric acid) in an amount from        about 7 to about 9 mg/mL of solution to adjust pH from about 3.5        to about 5.    -   (4) base to adjust pH, preferably an alkali metal hydroxide,        preferably NaOH in an amount to adjust pH from about 4 to 4.6.    -   (5) water qs to 1 mL.

The aripiprazole injectable formulation of the invention may be preparedas follows: Tartaric acid or other acid buffer is dissolved in water forinjection. The substituted-β-cyclodextrin (preferably SBECD) isdissolved in the acid buffer-water solution. Aripiprazoie is thendissolved in the solution. The pH of the solution is adjusted to withinthe range from about 3.5 to about 5, preferably about 4.3 by addingbase, such as sodium hydroxide or other alkali metal hydroxide oralkaline earth metal hydroxide. Additional water for injection is addedto obtain the desired batch volume.

The resulting solution is aseptically filtered, for example, through a0.22μ, membrane filter and filled into vials. The vials are stopped andsealed and terminally sterilized.

The aqueous injectable formulation of the invention will provide anamount of aripiprazole of at least 2 mg aripiprazole/mL, preferably atleast 5 mg aripiprazole/mL, when the amount of aripiprazole provided bythe complex is measured at a cyclodextrin concentration of 5% w/v inwater.

The aripiprazole formulations of the invention are used to treatschizophrenia in human patients. The preferred dosage employed for theinjectable formulations of the invention will be a 2 ml injectioncontaining 7.5 mg aripiprazole/mL or a dose of 15 mg given three timesdaily at two hour intervals, The injectable formulation is preferablyadministered intramuscularly although subcutaneous and intravenousinjections are effective as well.

The following example represents a preferred embodiment of theinvention.

EXAMPLE

A clear colorless aripiprazole injectable solution (2 mgaripiprazole/mL, mg/vial) essentially free of particulate matter byvisual inspection was prepared as follows.

A stainless steel hatching vessel was charged with an appropriate amountof water for injection USP.

With continuous stirring, 78 g tartaric acid granular USP and 1500 gsulfobutyl ether β-cyclodextrin (SBECD) was added to the batching vesseland was dissolved in the water.

Aripiprazole 20 g was added to the batching vessel and stirring wascontinued until the aripiprazole was dissolved.

Sodium hydroxide 1N was added to the above solution to adjust the pHthereof to about 4.3.

Additional water for injection USP was added to the above solution toadjust to the final batch size to 10 L with stirring.

The above solution was aseptically filtered through a 0.22 μM membranefilter into a sterilized container 4 mg amounts of the above solutionwere aseptically filled into sterilized vials which were thenaseptically stoppered with sterilized stoppers to seal the vials.

What is claimed is:
 1. An aqueous injectable formulation having a pH offrom about 3.5 to about 5, comprising: a) a complex comprisingaripiprazole and sulfobutyl ether-β-cyclodextrin; b) tartaric acid; c)sodium hydroxide; and d) water for injection.
 2. The formulation asdefined in claim 1 which contains 2 mg aripiprazole/ml 5 mgaripiprazole/ml or 7.5 mg aripiprazole/ml.
 3. The formulation as definedin claim 1 having a pH of about 4.3.
 4. The formulation as defined inclaim 1 comprising from about 0.1 to about 2.5% by weight aripiprazole.5. The formulation as defined in claim 1 comprising from about 0.2 toabout 1.5% by weight aripiprazole.
 6. The formulation as defined inclaim 1 wherein the sulfobutyl ether-β-cyclodextrin is present in anamount from about 100 to about 700 mg/ml of solution.
 7. The formulationas defined in claim 1 wherein the tartaric acid is present in an amountfrom about 7 to about 9 mg/ml.
 8. The formulation as defined in claim 1wherein the tartaric acid and the sodium hydroxide are present inamounts to impart a pH of about 4.3 to the formulation.